Deciphering the complex metabolic and molecular basis of cerebral ischemia and using this knowledge to develop therapeutic strategies for stroke treatment and rehabilitation is the theme of this competitive renewal application from the Interdepartment Stroke Program Project at the MGH. To this end, three (3) projects, plus one (1) Scientific and one (1) Administrative Core are proposed. Project 1 (Michael Moskowitz) continues to explore the role of nitric oxide in the cerebrovasculature and will expand preliminary data describing the therapeutic merits of eNOS up-regulation in wild type and in endothelial NOS knockout mice using a novel treatment strategy, chronic HMG-CoA reductase inhibition. Project 2 (Joseph Bonventre) will examine and characterize the importance of phospholipase A2 in normal and ischemic brain using recently cPLA2-/- mice. TO this end, he will evaluate in vivo the mechanisms of protection documented in this mutant mouse, and the role of cPLA2 in excitotoxic brain damage. Additional studies will explore the importance of cPLA2 interacting protein (PLIP) and evaluate the role of this protein in neuronal injury and glutamate release. Project 3 (Seth Finklestein) will continue to explore the importance of basic FGF on stroke recovery. These studies will be the first to extend the Stroke Program Project to investigate recovery of function, particularly as it relates to new neuronal sprouting and synap formation in the ischemic brain. Each of the projects will utilize the Scientific-Imaging Core (Bruce Rosen, Bradley Hyman) using state-of-the-art techniques in MR and morphometry. The approach taken is multi-disciplinary, interdepartmental, represents a logical extension of work accomplished during the previous funding period, incorporates new and exciting developments in molecular biology and genetics, introduces young promising scientists to the field of stroke (Drs. Liao, Hyman) and incorporates state-of-the-art imaging tools to examine the consequences of ischemia on brain metabolism, blood flow, tissue survival and recovery.